Background: Quantitative estimation of toxicokinetic variability in the human population is a persistent challenge in risk assessment of environmental chemicals. Traditionally, interindividual differences in the population are accounted for by default assumptions or, in rare cases, are based on human toxicokinetic data.
Objectives: We evaluated the utility of genetically diverse mouse strains for estimating toxicokinetic population variability for risk assessment, using trichloroethylene (TCE) metabolism as a case study.
Methods: We used data on oxidative and glutathione conjugation metabolism of TCE in 16 inbred and 1 hybrid mouse strains to calibrate and extend existing physiologically based pharmacokinetic (PBPK) models. We added one-compartment models for glutathione metabolites and a two-compartment model for dichloroacetic acid (DCA). We used a Bayesian population analysis of interstrain variability to quantify variability in TCE metabolism.
Results: Concentration–time profiles for TCE metabolism to oxidative and glutathione conjugation metabolites varied across strains. Median predictions for the metabolic flux through oxidation were less variable (5-fold range) than that through glutathione conjugation (10-fold range). For oxidative metabolites, median predictions of trichloroacetic acid production were less variable (2-fold range) than DCA production (5-fold range), although the uncertainty bounds for DCA exceeded the predicted variability.
Conclusions: Population PBPK modeling of genetically diverse mouse strains can provide useful quantitative estimates of toxicokinetic population variability. When extrapolated to lower doses more relevant to environmental exposures, mouse population-derived variability estimates for TCE metabolism closely matched population variability estimates previously derived from human toxicokinetic studies with TCE, highlighting the utility of mouse interstrain metabolism studies for addressing toxicokinetic variability.
1National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC, USA; 2The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina, USA; 3Department of Statistics and Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA; 4Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Recommended Citation:
Weihsueh A. Chiu,1 Jerry L. Campbell Jr.,2 Harvey J. Clewell III,et al. Physiologically Based Pharmacokinetic (PBPK) Modeling of Interstrain Variability in Trichloroethylene Metabolism in the Mouse[J]. Environmental Health Perspectives,2014-01-01,Volume 122(Issue 5):456